Chemical Properties
Brownish Orange Solid
Uses
Riocguat is used in the treatment for pulmonary hypertension.
Description
In September 2013, Health Canada approved riociguat (also referred to as BAY 63-2521), for the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment or inoperable CTEPH and for the treatment of adults with pulmonary arterial hypertension (PAH). Riociguat has a dual mode of action and works by (a) sensitizing sGC to the body’s NO by stabilizing NO–sGC binding and (b) an NO-independent, direct stimulation of sGC via a different binding site. This process restores the NO–sGC–cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.
Headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation were the most common adverse events ( 3%) observed during riociguat clinical trials. Riociguat comes with a black box warning for embryo-fetal toxicity.
Originator
Bayer (Germany)
Definition
ChEBI: A carbamate ester that is the methyl ester of {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamic acid. It is used for treatment of chronic thromboembolic pulmonary hypertension an
pulmonary arterial hypertension
Clinical Use
Guanylate cyclase stimulator:
Treatment of chronic thromboembolic pulmonary
hypertension (CTEPH) and pulmonary arterial
hypertension (PAH)
Synthesis
The sequence began with condensation of commercial 2-fluorobenzylhydrazine
(136) with sodium ethyl cyanopyruvate (137),
which derives from diethyl oxalate to generate aminopyrazole
138. This was followed by the cyclocondensation with 3-dimethylaminoacrolein
(139) to access pyrazolopyridine 140 in 50% yield
for the two-step operation. Next, ester 140 was transformed to
the corresponding primary amide 141, which was subsequently
dehydrated upon treatment with trifluoroacetic acid anhydride
(TFAA) to construct nitrile 142 in quantitative yield from 140.
Subjection of cyanopyrazole 142 to Pinner conditions using
methoxide and ammonium chloride in refluxing acetic acid generated
amidine 143, and this was followed by condensation with the
malononitrile derivative 144 in base to provide pyrimidine 145 in
73% yield. Hydrogenative cleavage of the phenyldiazine converted 145 to the pyrimidyl triamine 146, which underwent carbamoylation
at the 40 position to produce the penultimate carbamate
147. This carbamate was then selectively methylated
through deprotonation of the carbamate N¨CH proton followed by
quench with methyl iodide. Sequential recrystallization from
warm DMSO and refluxing ethyl acetate produced riociguat (XIX)
in 64% yield from 147.
Drug interactions
Potentially hazardous interactions with other drugs
Avanafil, sildenafil, tadalafil, vardenafil: enhanced
hypotensive effect - avoid.
Nicorandil: possibly enhanced hypotensive effect -
avoid.
Nitrates: possibly enhanced hypotensive effect -
avoid.
Metabolism
N-demethylation, catalysed by CYP1A1, CYP3A4,
CYP2C8 and CYP2J2 is the major biotransformation
pathway leading to its major circulating active
metabolite M-1 (pharmacological activity: 1/10th to
1/3rd of riociguat) which is further metabolised to the
pharmacologically inactive N-glucuronide.
Riociguat and metabolites are excreted via both
renal (33-45%) and biliary/faecal routes (48-59%).
Approximately 9-44% of the administered dose was
found as unchanged riociguat in faeces.
